Pathogenesis of emphysema: molecular mechanisms underlying cigarette smoke-induced cell death

Cigarette smoking is the major aetiological factor in the development of Chronic Obstructive Pulmonary Disease (COPD), a collection of diseases encompassing chronic bronchitis and emphysema. Emphysema is characterised by enlargement of the distal airspaces in the lungs due to destruction of alveolar walls, and was initially thought to be the result of matrix destruction from a protease-antiprotease and oxidant-antioxidant imbalance, leading to detachment of alveolar cells. However, recently apoptosis has been implicated in alveolar cell loss; increased numbers of apoptotic epithelial and endothelial cells have been observed in the lungs of emphysema patients. Thus the effect of cigarette smoke on apoptotic cell death was investigated.Unexpectedly, cigarette smoke condensate (CSC) did not induce apoptosis in either an alveolar epithelial type II cell line (A549) or primary human umbilical vein endothelial cells (HUVECs), but instead it induced necrosis and inhibited staurosporine-induced apoptosis. The anti-apoptotic, pro-necrotic, effect of CSC was reproduced in a model system using Jurkat T cells, when either staurosporine or Fas ligation was used as an apoptotic stimulus. Additional studies indicated that these effects might be oxidantmediated as the antioxidant compounds glutathione and dithiothreitol prevented CSCmediated apoptosis inhibition, and necrosis. Time course experiments revealed that CSC inhibited an early step in the caspase cascade, whereby caspase-3 was not activated. Moreover, reconstitution of the apoptosome in cytoplasmic extracts from CSC-treated cells, by addition of cytochrome-c and dATP, did not result in activation of caspases-3 or -9. Thus, smoke treatment may alter the levels of pro- and antiapoptogenic factors downstream of the mitochondria to inhibit active apoptosome formation. Therefore these data demonstrate that CSC treatment did not induce apoptosis as previously reported. More interestingly, CSC inhibited apoptosis by preventing activation of caspases, resulting in necrotic cell death. Thus, cell death in response to cigarette smoke by necrosis, and not apoptosis, may be responsible for the loss of alveolar walls observed in emphysema